Cerebrolysin for the Treatment of Aneurysmal

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BRIEF REPORT

Cerebrolysin for the Treatment of Aneurysmal

Subarachnoid Hemorrhage in Adults: A Retrospective Chart Review

Yung Ki Park.Hyeong-Joong Yi.Kyu-Sun Choi.Young-Jun Lee. Dong-Won Kim.Sae Min Kwon

Received: July 10, 2018/Published online: November 9 2018 ÓThe Author(s) 2018, corrected publication 2019

ABSTRACT

Introduction: Cerebrolysin is a neuroprotective drug used in the treatment of acute ischemic stroke. To our knowledge, this drug has never been evaluated in patients with aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to evaluate the effect of Cere- brolysin in patients with aneurysmal SAH.

Methods: Aneurysmal SAH patients who had their aneurysm obliterated at our institution from 2007 to 2016 were retrospectively studied.

Patients received Cerebrolysin treatment or standard care only (control group). Subgroup analyses were performed according to Hunt and Hess grade (good gradeB2, N = 216; poor gradeC3, N= 246) and treatment procedure (clip or coil).

Results: In good-grade patients (N = 216), clinical outcomes and mortality did not differ significantly between the control and Cere- brolysin groups. In poor-grade patients (N = 246), the mortality rate was significantly lower in the Cerebrolysin group (8.7%) than in the control group (25.4%, p= 0.006). In patients who received microsurgical clipping (N = 328), the mortality rate was significantly lower in the Cerebrolysin group (7.3%) than in the control group (18.5%,p= 0.016).

Conclusion: Cerebrolysin injection during the acute period of SAH appeared to reduce the mortality rate, especially in poor-grade patients.

This study suggests the potential of Cere- brolysin for treating aneurysmal SAH. Further studies are needed to confirm our results.

Keywords: Aneurysmal subarachnoid hemorrhage; Brain hemorrhage; Cerebrolysin;

Cerebrovascular disorders; Neuroprotective agents; Mortality

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Y. K. Park

Department of Neurosurgery, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea

H.-J. Yi (&)K.-S. Choi

Department of Neurosurgery, Hanyang University Medical Center, Seoul, Republic of Korea

e-mail: [email protected] Y.-J. Lee

Department of Radiology, Hanyang University Medical Center, Seoul, Republic of Korea D.-W. Kim

Department of Anesthesiology and Pain Medicine, Hanyang University Medical Center, Seoul, Republic of Korea

S. M. Kwon

Department of Neurosurgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea

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Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease with high morbidity and mortality. However, treatment remains insuffi- cient, and drugs to improve patient outcomes are not well established. SAH is a complex pathology and involves vasospasm, acute or chronic hydrocephalus, systemic inflammation, and stressful treatments including surgical procedures. Many agents such as clazosentan, simvastatin, and magnesium sulfate have been assessed in large clinical studies; however, in clinical practice the effects have been disap- pointing [1–3].

Cerebrolysin (EVER Neuro Pharma^TM) is a neuropeptide preparation that mimics the action of endogenous neurotrophic factors in brain protection and recovery. It has been shown to be effective against excitotoxicity, inhibits free radical formation, has neurotrophic activity, improves cellular survival, and stimulates sprouting, synaptogenesis, and neurogenesis [4–9]. Several clinical studies have shown beneficial effects of Cerebrolysin in stroke, dementia, and traumatic brain injury [10–13]. A recent meta-analysis of nine randomized, double-blind, placebo-controlled stroke studies with 1879 patients confirmed the early beneficial effect of Cerebrolysin on global neurologic deficits [14]. Recently, Cerebrolysin has been successfully tested for its neurorecov- ery potential in patients with moderate-to-severe strokes with treatment initiation in the acute and subacute phase [11,15,16].

This study investigated potential benefits of Cerebrolysin in patients with aneurysmal SAH.

To our knowledge, no such studies have been performed with Cerebrolysin before.

METHODS

Study Design

We retrospectively reviewed medical charts from patients with SAH who underwent aneurysmal occlusion at our institution between January 2007 and December 2016.

There was no significant change in surgical or

SAH within 48 h before admission, and (3) aneurysm obliterated with either clip or coil within 72 h after SAH. Exclusion criteria were early death within 72 h of admission, procedural complication, patients who discontinued Cerebrolysin treatment within 3 days, previous stroke or neurologic deficits, mental disability, psychologic disorders, or lost to follow-up within 3 months. All procedures performed in this study were in accordance with the ethical standards of the institution and with the 1964 Helsinki Declaration and its later amendments.

For this type of study, formal consent is not required. This study is not registered as a clinical trial because of its retrospective design. This study was approved by the institutional review board at the author’s institute (HYUH IRB 2017-10-007-001).

Treatment Groups

Patients received Cerebrolysin treatment or standard care only (control group). Cerebrolysin was administered at daily doses of 30 ml for at least 3 days. Cerebrolysin was diluted in 1000 ml normal saline and was administered as a slow intravenous infusion over 24 h. Treat- ment was initiated within 48 h after SAH.

Data Collection

Demographic information, radiologic findings, treatment, and clinical parameters were reviewed. These data included sex, age, hypertension, diabetes mellitus, treatment (clip or coil), and circulation (anterior or posterior). The Glasgow Coma Scale (GCS) and Hunt and Hess grade [17] were used to record each patient’s initial condition. The modified Fisher Scale, concomitant intracerebral hemorrhage (ICH), SAH sum score [18], and intraventricular hemorrhage (IVH) sum score [19] were recorded to evaluate initial radiologic findings. SAH sum score (0–30) was calculated as the mean of the Hijdra score, which is the sum of the amount of blood in ten cistern or fissure points (0–3 each).

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Table 1 Demographic features, radiologic ﬁndings, and clinical outcomes in total SAH patients

Control (N= 328) Cerebrolysin (N= 134) pvalue

Female 221 (67.4%) 84 (62.7%) 0.391

Age (years) 55.0 [47.0; 66.0] 56.0 [48.0; 62.0] 0.876

Operation type

Clip 232 (70.7%) 96 (71.6%) 0.934

Coil 96 (29.3%) 38 (28.4%)

Circulation

Anterior 294 (89.6%) 124 (92.5%) 0.430

Posterior 34 (10.4%) 10 (7.5%)

Hunt and Hess grade

Grade 1 25 (7.6%) 9 (6.7%) 0.567

Grade 2 126 (38.4%) 56 (41.8%)

Grade 3 93 (28.4%) 34 (25.4%)

Grade 4 79 (24.1%) 30 (22.4%)

Grade 5 5 (1.5%) 5 (3.7%)

Modiﬁed Fisher scale

1 31 (9.5%) 12 (9.0%) 0.096

2 5 (1.5%) 5 (3.7%)

3 119 (36.3%) 35 (26.1%)

4 173 (52.7%) 82 (61.2%)

GCS score 13.0 [9.5; 15.0] 14.0 [8.0; 15.0] 0.964

Concomitant ICH 94 (28.7%) 47 (35.1%) 0.212

Bicaudate index 17.6 [14.9; 20.2] 15.7 [13.9; 18.3] \0.001*

SAH sum score 19.0 [11.0; 26.0] 25.0 [14.0; 28.0] 0.002*

IVH sum score 1.0 [0.0; 4.0] 1.0 [0.0; 3.0] 0.375

Smoking 86 (26.2%) 39 (29.1%) 0.604

Hypertension 126 (38.4%) 49 (36.6%) 0.790

Diabetes mellitus 19 (5.8%) 14 (10.4%) 0.118

Permanent shunt operation 47 (14.3%) 21 (15.7%) 0.822

Angiographic vasospasm 100 (30.5%) 55 (41.0%) 0.038*

Delayed cerebral ischemia 43 (13.1%) 23 (17.2%) 0.325

Days of Cerebrolysin 0.0 [0.0; 0.0] 13.0 [10.0; 20.0]

Length of stay (days) 24.0 [16.0; 47.0] 22.0 [15.0; 46.0] 0.289

mRS 2.0 [1.0; 5.0] 2.0 [1.0; 5.0] 0.398

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IVH sum score (0–12) was calculated as the mean Graeb score, which is the sum of the score for each ventricle (lateral ventricles, 0–4; third ventricle, 0–2; fourth ventricle, 0–2). Chronic hydrocephalus leading permanent shunt operation was reviewed. Angiographic vasospasm was defined as[50% decrease of the intracranial artery diameter by imaging or diagnostic angiography. Delayed cerebral ischemia was defined as the occurrence of focal neurologic impairment or a decrease of at least two points on the GCS score or one of its individual com- ponents lasting at least 1 h that could not be attributed to other causes [20]. A blinded neu- roradiologist at our institution recorded radiologic findings. The modified Rankin Scale (mRS) was used to evaluate clinical outcome 3 months after SAH [21]. Mortality was defined as in- hospital death later than 72 h after SAH ictus.

Treatment of SAH Patients

All patients had their aneurysm obliterated by either microscopic aneurysm neck clipping or endovascular coil embolization with or without stent assist. The therapy was chosen by the neurovascular team based on age, mental status, aneurysm location, size, and neck/dome pre- sentation. All patients with posterior circulation including the vertebral and basilar arteries were treated with endovascular coil embolization.

Blood pressure and glucose were managed strictly with close observation according to our institution’s protocol. Patients in the Cere- brolysin group were not treated any differently from the control group except for Cerebrolysin.

Patient Group Classification

Subgroup analyses were performed according to the severity of subarachnoid hemorrhage clas- sified by the Hunt and Hess grade (good grade B2, N= 216; poor gradeC 3, N= 246) and treatment procedure (clipping, coiling).

Statistical Analysis

Non-parametric data were compared with chi- square and Fisher’s exact tests. Parametric variables with a normal distribution were compared by independent ttest and those without a normal distribution by Mann-Whitney U test.

Descriptive summaries were reported as mean (±standard deviation) for continuous variables with normal distribution, median [interquartile range (IQR)] for continuous variables without normal distribution, and frequency (percent- age) for categorical variables. All data were analyzed with R version 3.3.2 (https://www.r- project.org/; R Foundation for Statistical Com- puting, Vienna, Austria).

RESULTS

Total Aneurysmal SAH Patients

Overall, 548 aneurysmal SAH patients were treated at our institution from 2007 to 2016; of these, 462 patients were included in this study.

Patients were excluded because of early death within 72 h (N= 15), procedural complication (N = 8), previous neurologic deficits (N= 9), Clinical outcome

Favorable (mRS 0–2) 181 (55.2%) 70 (52.2%) 0.636

Unfavorable (mRS 3–6) 147 (44.8%) 64 (47.8%)

Mortality 57 (17.4%) 12 (9.0%) 0.031*

SAH subarachnoid hemorrhage,GCS Glasgow Coma Scale,ICH intracerebral hemorrhage,IVHintraventricular hemorrhage, mRSmodiﬁed Rankin scale

*Indicates statistical signiﬁcance (p\0.05)

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Table 2 Demographic features, radiologic ﬁndings, and clinical outcomes in good-grade SAH patients

Female 104 (68.9%) 39 (60.0%) 0.268

Age 53.0 [44.0; 64.0] 55.0 [47.0; 59.0] 0.581

Operation type

Clip 103 (68.2%) 45 (69.2%) 1.000

Coil 48 (31.8%) 20 (30.8%)

Circulation

Anterior 141 (93.4%) 61 (93.8%) 1.000

Posterior 10 (6.6%) 4 (6.2%)

Hunt and Hess grade

Grade 1 25 (16.6%) 9 (13.8%) 0.766

Grade 2 126 (83.4%) 56 (86.2%)

1 27 (17.9%) 9 (13.8%) 0.357

2 2 (1.3%) 2 (3.1%)

3 66 (43.7%) 23 (35.4%)

4 56 (37.1%) 31 (47.7%)

GCS score 15.0 [15.0; 15.0] 15.0 [15.0; 15.0] 0.761

Concomitant ICH 23 (15.2%) 14 (21.5%) 0.352

Bicaudate index 16.7 [14.5; 19.4] 15.8 [14.1; 17.7] 0.043*

SAH sum score 14.0 [8.0; 22.0] 17.0 [10.0; 27.0] 0.051

IVH sum score 0.0 [0.0; 1.0] 1.0 [0.0; 2.0] 0.106

Smoking 40 (26.5%) 21 (32.3%) 0.480

Hypertension 46 (30.5%) 24 (36.9%) 0.440

Permanent shunt 15 (9.9%) 5 (7.7%) 0.791

Angiographic vasospasm 49 (32.5%) 19 (29.2%) 0.758

Length of stay (days) 22.0 [17.0; 34.0] 18.0 [15.0; 26.0] 0.015*

mRS 1.0 [1.0; 2.0] 1.0 [0.0; 2.0] 0.145

Clinical outcome

Favorable (mRS 0–2) 119 (78.8%) 50 (76.9%) 0.898

Unfavorable (mRS 3–6) 32 (21.2%) 15 (23.1%)

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discontinuation of Cerebrolysin within 3 days (N= 19), and follow-up loss within 3 months (N= 35). Of 462 patients with SAH, 134 were included in the Cerebrolysin group and 328 in the control group. Demographic features, radiologic findings, and clinical outcomes are pre- sented in Table1. Median treatment duration with Cerebrolysin was 13 [10.0; 20.0] days.

Baseline parameters did not differ between groups except for the initial bicaudate index, which was higher in the control group (median;

17.6 vs. 15.7, p\0.001) and for the SAH sum score, which was higher in the Cerebrolysin group (median; 25.0 vs. 19.0, p= 0.002).

Angiographic vasospasm occurred more often in the Cerebrolysin group than in the control group (41.0 vs. 30.5, p= 0.038). Three months after SAH, patients of both groups had a median mRS score of 2; the mortality rate was significantly higher in the control group (17.4%) than in the Cerebrolysin group (9.0%,p= 0.031).

Good-Grade SAH Patients (Hunt and Hess Grade£2)

Of 216 patients with Hunt and Hess gradeB2, 65 were included in the Cerebrolysin group and 151 in the control group. Demographic features, radiologic findings, and clinical outcomes are shown in Table2. Median treatment duration with Cerebrolysin was 12 [9.0; 17.0] days.

Baseline parameters did not differ between groups except for the initial bicaudate index, which was significantly higher in the control group (median; 16.7 vs. 15.8,p= 0.043). Length of stay was significantly reduced by 4 days in the Cerebrolysin group, with statistical signifi- cance (22 vs. 18 median days,p= 0.015). Three months after SAH, patients of both groups had a

median mRS score of 1; no significant group differences were reported for mortality.

Poor-Grade SAH Patients (Hunt and Hess Grade‡3)

Of 246 patients with Hunt and Hess gradeC3, 69 were included in the Cerebrolysin group and 177 in the control group. Demographic features, radiologic findings, and clinical outcomes are shown in Table3. Median treatment duration with Cerebrolysin was 14 [12.0; 21.0] days.

Baseline parameters did not differ between groups except for the initial bicaudate index, which was significantly higher in the control group (median; 18.1 vs. 15.7,p= 0.001) and for the SAH sum score, which was significantly higher in the Cerebrolysin group (median; 27.0 vs. 25.0, p= 0.001). Angiographic vasospasm occurred more often in the Cerebrolysin group compared with the control group (52.2% vs.

28.8%, p= 0.001). Three months after SAH, patients of both groups had a median mRS score of 4; the mortality rate was significantly higher in the control group (25.4%) than in the Cere- brolysin group (8.7%,p= 0.006).

Clip and Coil Patients

Of 462 patients, 328 (71.0%) had microsurgical aneurysm neck clipping and 134 (29.0%) had endovascular coil embolization. Demographic features, radiologic findings, and clinical outcomes are shown in Table4. In clip patients, the initial bicaudate index was significantly higher in the control group (median; 17.5 vs. 15.5, p\0.001) and the SAH sum score was significantly higher in the Cerebrolysin group (median; 25.0 vs. 19.0, p= 0.007). Angiographic

Mortality 12 (7.9%) 6 (9.2%) 0.964

SAH subarachnoid hemorrhage,GCS Glasgow Coma Scale,ICH intracerebral hemorrhage,IVHintraventricular hemorrhage, mRSmodiﬁed Rankin Scale

*Indicates statistical signiﬁcance (p \0.05)

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Table 3 Demographic features, radiologic ﬁndings, and clinical outcomes in poor-grade SAH patients

Female sex 117 (66.1%) 45 (65.2%) 1.000

Age 56.0 [49.0; 68.0] 56.0 [50.0; 65.0] 0.599

Operation type

Clip 129 (72.9%) 51 (73.9%) 0.997

Coil 48 (27.1%) 18 (26.1%)

Circulation

Anterior 153 (86.4%) 63 (91.3%) 0.406

Posterior 24 (13.6%) 6 (8.7%)

Hunt and Hess grade

Grade 3 93 (52.5%) 34 (49.3%) 0.286

Grade 4 79 (44.6%) 30 (43.5%)

Grade 5 5 (2.8%) 5 (7.2%)

1 4 (2.3%) 3 (4.3%) 0.133

2 3 (1.7%) 3 (4.3%)

3 53 (29.9%) 12 (17.4%)

4 117 (66.1%) 51 (73.9%)

GCS score 11.0 [6.0; 13.0] 8.0 [6.0; 13.0] 0.447

Concomitant ICH 71 (40.1%) 33 (47.8%) 0.339

Bicaudate index 18.1 [15.3; 21.3] 15.7 [13.7; 18.8] 0.001*

SAH sum score 25.0 [14.0; 27.0] 27.0 [23.0; 29.0] 0.001*

IVH sum score 2.0 [0.0; 5.0] 2.0 [1.0; 4.0] 0.994

Smoking 46 (26.0%) 18 (26.1%) 1.000

Hypertension 80 (45.2%) 25 (36.2%) 0.257

Permanent shunt 32 (18.1%) 16 (23.2%) 0.466

Angiographic vasospasm 51 (28.8%) 36 (52.2%) 0.001

Length of stay (days) 30.0 [15.0; 67.0] 33.0 [16.0; 70.0] 0.547

mRS 4.0 [2.0; 6.0] 4.0 [2.0; 5.0] 0.525

Clinical outcome

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vasospasm developed more often in the Cere- brolysin group (33.6% vs. 47.9%, p= 0.021), and delayed cerebral ischemia was not statisti- cally different between groups (12.5% vs.

20.8%,p= 0.079). Three months after SAH, the mortality rate was significantly lower in the Cerebrolysin group (median; 7.3% vs. 18.5%, p= 0.016). No significant group differences were observed in the mRS. Coil patients did not differ in baseline characteristics or outcome parameters.

Safety

The median treatment duration with Cere- brolysin was 13.0 days. Table5shows the rate of adverse events with severe intensity for both groups. The most common adverse event was pneumonia followed by urinary tract infection, acute renal failure, and myocardial infarction.

There was no significant difference between the two groups.

DISCUSSION

The current study showed excellent outcomes in both study groups and a similar low mortality rate in SAH patients with good grade according to Hunt and Hess. In contrast, in patients with poor grade, the mortality rate was significantly higher in the control group (25.4% versus 8.7%) than in Cerebrolysin-treated patients. These findings are reminiscent of previous studies showing beneficial effects of Cerebrolysin especially in more severely affected patients of different brain pathologies. The results of the

CASTA trial reported a reduced mortality rate in more severely affected ischemic stroke patients treated with Cerebrolysin [22]. Similarly, Khalili et al. showed that Cerebrolysin is associated with improved functional recovery, decreased mortality rate, and better outcome in patients with severe disability after traumatic brain injury [23].

Of note, our study showed a lower mortality rate in the Cerebrolysin group in patients with microsurgical clipping but not in patients with endovascular coiling. This might be because surgical clipping was more frequently performed in patients with higher Hunt and Hess grades and in patients with concomitant ICH because of the advantage of evacuating the hematoma simultaneously. Although angiographic vasospasm and delayed cerebral ischemia occurred more often in poor-grade SAH patients treated with Cerebrolysin, the mortality rate was higher in the control group.

Inhibition of brain edema seems to be a key mechanism for lowering the mortality rate in the acute phase after SAH. Maintaining the blood-brain barrier integrity can reduce vaso- genic edema, and anti-inflammatory effects contribute to decreased cytotoxic edema [24].

An intracranial hemorrhage rat model showed that Cerebrolysin inhibited brain edema and the inflammatory response and protected the integrity of the blood-brain barrier [10]. In a mouse stroke model study, Cerebrolysin inhibited the effect of proinflammatory mediators such as TNF-a, IL-1b, IL-6, and NF-jB [21, 22].

Unfortunately, we could not assess the effect of Cerebrolysin on brain edema formation in the

Favorable (mRS 0–2) 62 (35.0%) 20 (29.0%) 0.452

Unfavorable (mRS 3–6) 115 (65.0%) 49 (71.0%)

Mortality 45 (25.4%) 6 (8.7%) 0.006*

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Table 4 Demographic features, radiologic ﬁndings, and clinical outcomes by operation type (clip versus coil)

Clip (N= 328) Coil (N= 134)

Control (N= 232)

Cerebrolysin (N= 96)

p Control

(N= 96)

p

Female 155 (66.8%) 59 (61.5%) 0.424 66 (68.8%) 25 (65.8%) 0.900

Age 55.0 [48.0; 66.0] 55.0 [49.0; 61.5] 0.601 55.1 ±13.3 56.4±14.4 0.639 Circulation

Anterior 232 (100.0%) 96 (100.0%) 62 (64.6%) 28 (73.7%) 0.420

Posterior 0 (0.0%) 0 (0.0%) 34 (35.4%) 10 (26.3%)

Hunt and Hess grade 3.0 [2.0; 4.0] 3.0 [2.0; 4.0] 0.778 2.5 [2.0; 3.0] 2.0 [2.0; 3.0] 0.832 Modiﬁed Fisher scale

1 and 2 22 (9.5%) 11 (11.5%) 0.734 14 (14.6%) 6 (15.8%) 1.000

3 and 4 210 (90.5%) 85 (88.5%) 82 (85.4%) 32 (84.2%)

GCS score 13.0 [8.0; 15.0] 13.0 [7.0; 15.0] 0.843 14.0 [12.0;

15.0]

14.0 [9.0; 15.0] 0.872

Bicaudate index 17.5±3.9 15.5 ±3.2 \0.001* 17.8 [15.1;

20.8]

16.9 [14.8; 21.8] 0.706

SAH sum score 19.0 [12.0; 26.0] 25.0 [14.0; 28.0] 0.007* 17.5 [8.5; 26.0] 23.0 [11.0; 28.0] 0.102 IVH sum score 1.0 [0.0; 4.0] 1.0 [0.0; 2.0] 0.989 1.0 [0.0; 4.0] 2.0 [0.0; 6.0] 0.099

Concomitant ICH 81 (34.9%) 41 (42.7%) 0.229 13 (13.5%) 6 (15.8%) 0.951

Smoking 66 (28.4%) 20 (20.8%) 0.197 29 (30.2%) 10 (26.3%) 0.813

Hypertension 82 (35.3%) 37 (38.5%) 0.673 44 (45.8%) 12 (31.6%) 0.189

Diabetes mellitus 16 (6.9%) 11 (11.5%) 0.251 3 (3.1%) 3 (7.9%) 0.459

Permanent shunt 38 (16.4%) 17 (17.7%) 0.896 9 (9.4%) 4 (10.5%) 1.000

Angiographic vasospasm

78 (33.6%) 46 (47.9%) 0.021* 22 (22.9%) 9 (23.7%) 1.000

Delayed cerebral ischemia

29 (12.5%) 20 (20.8%) 0.079 14 (14.6%) 3 (7.9%) 0.447

Length of stay (days) 27.0 [17.0; 60.0] 23.0 [16.0; 50.5] 0.372 20.0 [15.0;

33.5]

18.0 [14.0; 32.0] 0.407

mRS score 2.0 [1.0; 5.0] 3.0 [1.0; 5.0] 0.239 1.0 [1.0; 4.0] 2.0 [1.0; 4.0] 0.743 Clinical outcome

Favorable (mRS 0–2)

119 (51.3%) 46 (47.9%) 0.663 62 (64.6%) 24 (63.2%) 1.000

Unfavorable (mRS 3–6)

113 (48.7%) 50 (52.1%) 34 (35.4%) 14 (36.8%)

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current study, but it would be interesting to address this in future studies.

One of the limitations of this study was the retrospective design. Accordingly, data from medical records were limited and did not allow precise matching of patients in terms of baseline characteristics. Furthermore, treatment with Cerebrolysin was limited to the acute phase of SAH, and treatment duration varied between 8 and 21 days. For efficacy assessment, no data were available regarding functional disability or cognitive or neuropsychologic outcome. Due to the exclusion of patients who died within 72 h (N= 15), the mortality rate might have been slightly underestimated.

However, to our knowledge, this is the largest study that evaluated the effects of Cerebrolysin in aneurysmal SAH patients. Despite the limited level of evidence of this retrospective study, we

think that these results are promising and could provide guidance for future randomized studies evaluating the effect of Cerebrolysin on SAH patients.

CONCLUSIONS

Hemorrhagic stroke including aneurysmal SAH is a devastating disease causing severe bain damage. This study suggests a potential benefit of Cerebrolysin to reduce the mortality rate in patients with aneurysmal SAH, which should be further evaluated in clinical studies.

ACKNOWLEDGEMENTS

We thank the participants of this study.

Control (N= 232)

p Control

(N= 96)

p

Mortality 43 (18.5%) 7 (7.3%) 0.016* 14 (14.6%) 5 (13.2%) 1.000

Table 5 Comparison of adverse events of severe intensity between control and Cerebrolysin groups

Pneumonia 29 (8.84%) 12 (8.96%) 1.000

Urinary tract infection 18 (5.49%) 8 (5.97%) 0.986

CSF infection 3 (0.91%) 2 (1.49%) 0.630

Acute renal failure 17 (5.18%) 4 (2.99%) 0.434

Pulmonary embolism 5 (1.52%) 1 (0.75%) 0.678

Acute cholecystitis 0 (0.00%) 1 (0.75%)

Myocardial infarction 14 (4.29%) 5 (3.73%) 1.000

Severe adverse event 82 (25.0%) 31 (23.1%) 0.761

CSFcerebrospinal ﬂuid

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Funding. No funding or sponsorship was received for this study. EVER Pharmaceuticals funded the article processing charges and open access fee.

Authorship. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosure. Yung Ki Park, Hyeong-Joong Yi, Kyu-Sun Choi, Young-Jun Lee, Dong-Won Kim, and Sae Min Kwon have nothing to disclose.

Compliance with Ethics Guidelines. All procedures performed in this study were in accordance with the ethical standards of the institution and with the 1964 Helsinki Decla- ration and its later amendments. For this type of study, formal consent is not required. This study was approved by the institutional review board at the author’s institute (HYUH IRB 2017-10-007-001).

Data Availability. The data sets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Open Access. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/

by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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